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Platelet-Derived Growth Factor C Is Upregulated in Human Uterine Fibroids and Regulates Uterine Smooth Muscle Cell Growth1

机译:血小板衍生的生长因子C在人子宫肌瘤中上调并调节子宫平滑肌细胞的生长1

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摘要

Leiomyomata uteri (i.e., uterine fibroids) are benign tumors arising from the abnormal growth of uterine smooth muscle cells (SMCs). We show here that the expression of platelet-derived growth factor C (PDGFC) is higher in approximately 80% of uterine fibroids than in adjacent myometrial tissues examined. Increased expression of PDGFC is also observed in fibroid-derived SMCs (fSMCs) relative to myometrial-derived SMCs (mSMCs). Recombinant bioactive PDGFCC homodimer stimulates the growth of fSMCs and mSMCs in ex vivo cultures and prolongs the survival of fSMCs in Matrigel plugs implemented subcutaneously in immunocompromised mice. The knockdown of PDGF receptor-alpha (PDGFRA) through lentiviral-mediated RNA interference reduces the growth of fSMCs and mSMCs in ex vivo cultures and in Matrigel implants. Furthermore, two small molecule inhibitors of the PDGFR tyrosine kinase (i.e., imatinib and dasatinib) exerted negative effects on fSMC and mSMC growth in ex vivo cultures, albeit at concentrations that cannot be achieved in vivo. These results suggest that the PDGFCC/PDGFRA signaling module plays an important role in fSMC and mSMC growth, and that the upregulation of PDGFC expression may contribute to the clonal expansion of fSMCs in the development of uterine fibroids.
机译:子宫平滑肌瘤(即子宫肌瘤)是由子宫平滑肌细胞(SMCs)异常生长引起的良性肿瘤。我们在这里显示,血小板源性生长因子C(PDGFC)的表达在大约80%的子宫肌瘤中比在相邻的子宫肌层组织中更高。相对于肌层来源的SMC(mSMC),在肌瘤来源的SMC(fSMC)中也观察到PDGFC的表达增加。重组生物活性PDGFCC同型二聚体可刺激离体培养物中fSMC和mSMC的生长,并延长免疫受损小鼠皮下实施的Matrigel栓塞中fSMC的存活时间。通过慢病毒介导的RNA干扰降低PDGF受体-α(PDGFRA),可降低离体培养物中和基质胶植入物中fSMC和mSMC的生长。此外,PDGFR酪氨酸激酶的两种小分子抑制剂(即伊马替尼和达沙替尼)在离体培养物中对fSMC和mSMC的生长具有负面影响,尽管其浓度在体内无法实现。这些结果表明PDGFCC / PDGFRA信号传导模块在fSMC和mSMC生长中起重要作用,并且PDGFC表达的上调可能有助于子宫肌瘤发展中fSMC的克隆扩增。

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